chr12-865122-C-T

Position:

chr12-865122-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_213655.5(WNK1):c.2152C>T(p.Arg718Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,519,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 3.09

Variant links:

Genes affected

WNK1 (HGNC:14540): (WNK lysine deficient protein kinase 1) This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

WNK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.7 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.

BP4

Computational evidence support a benign effect (MetaRNN=0.3321278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.2152C>T	p.Arg718Cys	missense_variant	9/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 linkuse as main transcript	c.2139+2852C>T		intron_variant		ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.2152C>T	p.Arg718Cys	missense_variant	9/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.2139+2852C>T		intron_variant		1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.0000341

AC:

AN:

146764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000679

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000490

AC:

AN:

122564

Hom.:

AF XY:

0.0000452

AC XY:

AN XY:

66400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000422

Gnomad OTH exome

AF:

0.000267

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1372342

Hom.:

Cov.:

AF XY:

0.0000326

AC XY:

AN XY:

675438

show subpopulations

Gnomad4 AFR exome

AF:

0.0000637

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000563

Gnomad4 SAS exome

AF:

0.0000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000280

Gnomad4 OTH exome

AF:

0.0000522

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146764

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

71682

show subpopulations

Gnomad4 AFR

AF:

0.0000499

Gnomad4 AMR

AF:

0.0000679

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000305

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	WNK1: PM2, BP4 -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 718 of the WNK1 protein (p.Arg718Cys). This variant is present in population databases (rs786205473, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle weakness (PMID: 27671536). ClinVar contains an entry for this variant (Variation ID: 191028). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WNK1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 11, 2022	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2022

The p.R718C variant (also known as c.2152C>T), located in coding exon 9 of the WNK1 gene, results from a C to T substitution at nucleotide position 2152. The arginine at codon 718 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in an individual with limb-girdle muscular dystrophy (Monies D et al. Hum Genomics, 2016 Sep;10:32). This amino acid position is well conserved in available vertebrate species; however, cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

M_CAP

Benign

0.011

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

Sift4G

Benign

0.076

Vest4

0.46

MVP

0.15

ClinPred

0.82

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.027

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over